Comprehensive identification of FoxO signaling as a promising prognostic and immunotherapeutic biomarker in glioma

Convincing evidence suggests that FoxO signaling (FS) dysfunction is associated with cancer progression and tumorigenesis but its effect on the tumor microenvironment (TME) and immunotherapy response remains unclear. Here, we retrieved FS-related genes from the KEGG database, first analyzing their differential expression in 31 TCGA cancer types with matched Genotype-Tissue Expression (GTEx) normal tissue data. We then calculated FS scores via ssGSEA for 33 TCGA cancer types, systematically exploring their prognostic value and correlations with TME characteristics and immunotherapy response. High FS scores were consistently associated with an immunosuppressive TME and poorer OS across multiple tumor types. Analysis of the IMvigor210 immunotherapy cohort further revealed elevated FS scores correlated with anti-PD-1 treatment resistance. Focusing on gliomas, we identified FS-based molecular subtypes and constructed a PCA score that robustly predicted glioma prognosis and immune checkpoint inhibitor response. External validation was achieved in independent CGGA and GEO cohorts. Our findings indicate that FS is a key modulator of the immunosuppressive TME and support FS and PCA scores as potential prognostic and immunotherapeutic biomarkers for gliomas with their clinical utility pending experimental validation.